Catheter and associated system for pacing the heart

ABSTRACT

The apparatus comprises a probe having a tip portion, a first electrode mounted on a terminal free end of the tip portion and a second electrode spaced along the tip portion from the first electrode for supplying a reference potential. The probe is constructed so as to hold the first electrode in contact with tissue of an in vivo beating heart with a positive pressure without causing macroscopic damage to the heart tissue while orienting the probe such that the second electrode is spaced from the heart tissue. A stylet is retractably mounted within the probe, for allowing a physician to maneuver the probe through a vein or the like. Once the probe is in position, it may be replaced by a probe of a different shape. The probe may also be retracted while being inserted, for preventing internal injury to the patient. The stylet may have a noncircular cross-section for restricting directions in which it can bend. In an alternative embodiment, a combination catheter is disclosed, including pacing electrodes for pacing the heart while measuring the potentials thereof. The pacing electrodes of this embodiment are placed near the tip of the catheter, and circumferentially displaced from one another to form an electric dipole for pacing the heart, and in addition are relatively small, to minimize the potential threshold necessary to pace the heart. Such pacing electrodes may be used without the first and second electrodes for measuring potentials.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. patent application Ser. No. 07/972,870filed Nov. 5, 1992 (abandoned); which is a continuation of U.S. patentapplication Ser. No. 07/861,333 filed Mar. 30, 1992 (abandoned); whichis a continuation of U.S. patent application Ser. No. 07/579,801 filedSep. 10, 1990 (abandoned); which is a continuation-in-part of U.S.patent application Ser. No. 225,043 filed Jul. 27, 1988 (now U.S. Pat.No. 4,979,510 issued Dec. 25, 1990); which is a continuation-in-part ofU.S. patent application Ser. No. 038,974 filed Apr. 16, 1987, nowabandoned, which is a division of U.S. patent application Ser. No.586,697 filed Mar. 6, 1984, now U.S. Pat. No. 4,682,603, issued Jul. 27,1987.

This invention relates to the pacing of in vivo hearts, and moreparticularly to a method and apparatus for pacing a heart by contactingheart tissue with positive pressure from the tip of a catheter, and thenproviding pacing via electrodes displaced oppositely on a catheter inthe vicinity of the catheter tip. The following disclosure is in thecontext of the measurement of monophasic action potentials (MAPs) withinan in vivo heart, but the present invention is directed specifically tothe pacing of a heart without the measurement of such MAPs. Thecombination of pacing and measuring the MAPs is the subject of copendingU.S. patent application Ser. No. 332,875 filed Apr. 3, 1989, which isincorporated herein by reference and which is scheduled to issue on Sep.11, 1990 as U.S. Pat. No. 4,955,382. New disclosure is included in thisapplication, relating to the placement of the pacing electrodes near thetip of a catheter, and new FIG. 25 (discussed below) is submittedherewith to specifically show the embodiment to which the some of thepresent claims are directed. However, independent claim 1 and certaindependent claims are based upon the disclosure of the parent applicationSer. No. 225,043, referenced above.

The text of the present application is in large part identical to thatof the parent application, but for the additional text at the endrelating to FIG. 25 and related text in various parts of thespecification.

BACKGROUND OF THE INVENTION

Studies have been performed on tissues obtained from human hearts. Ithas been learned that a resting cardiac cell has a transmembrane voltagedifference of about 90 mV. The inside of the cell is negative relativeto the extracellular fluid and, upon cell stimulation, an actionpotential ensues. The action potential consists of five phases. Phase 0is rapid depolarization, phase 1 is an early repolarization, phase 2 isthe plateau phase, phase 3 is a rapid repolarization to the diastolictransmembrane voltage, and phase 4 is the diastolic period. Thetime-voltage course of the action potential varies among differentcardiac cell types.

The electrical charge of the outer membrane of individual heart musclecells is known as the membrane potential. During each heart beat, themembrane potential discharges (depolarizes) and then slowly recharges(repolarizes). The waveform of this periodic depolarization andrepolarization is called the "transmembrane action potential."Mechanistically, the action potential is produced by a well-organizedarray of ionic currents across the cell membrane.

The transmembrane action potential has typically been recorded by meansof microelectrodes, which are extremely fine glass capillaries that canbe impaled into a single heart muscle cell. Because of the fragility ofthe glass capillary and the small dimensions of the heart cell, suchrecordings can be obtained only in small isolated tissue preparations,which are excised from animal hearts and are pinned down in a chamberwith artificial solution. It is impossible to use the microelectrodetechnique in the intact beating heart, such as in patients.

Most of our knowledge about the electrophysiologic properties of theheart is based on the use of microelectrodes. However, because themicroelectrode cannot be used in the human heart, there has been a lackof data relating to the elementary processes in the in vivo human heart,which may be different from the processes of the in vitro heart,particularly in disease.

At the turn of the century, it had already been recognized that apotential similar in shape to the later-discovered transmembranepotential could be recorded if one electrode was brought into contactwith an injured spot of the heart and the other electrode with an intactspot. Those signals became known as "injury potential" or "monophasicaction potentials" (MAPs) because of the waveform shape. When it wasfound that the injury could be produced by suction, so-called suctionelectrodes were developed. Thus, to examine the time course of localelectrical activity under experimental conditions in whichmicroelectrode recordings are difficult or impossible to make, such asin the vigorous beating in-situ heart, investigators have often usedsuction electrodes. The signal obtained with suction electrodes ismonophasic and, although of smaller amplitude, accurately reflects theonset of depolarization and the entire repolarization phase oftransmembrane action potentials recorded from cells in the samevicinity. Suction electrodes have also been used in human subjects, butthe potential for subendocardial damage and S-T segment elevation haslimited its clinical use to short recording periods of two minutes orless. Because the shape and duration of the action potentials vary fromsite to site in the heart, longer recording time from a singleendocardial site is needed to evaluate long-term MAP changes, such asheart rate effects over several basic cycle lengths or in response topharmacologic interventions. These longer recording times have not beenachievable, however, with suction electrodes, because of the resultingdamage to the tissue. Primarily for this reason, the suction electrodetechnique has never gained wide clinical acceptance. Therefore, the gapbetween microelectrode studies in excised animal tissue and what ispossible in the intact human heart has remained large. There still wasno safe and reliable method to obtain such signals in the human heartitself, which could provide the most valuable information,without damageto the myocardium.

Applicants herein have recognized that local heart muscle injury is nota prerequisite for the generation of MAPs, and that application ofslight pressure with the tip against the inner wall of the heart wouldresult in monophasic elevations of the signal if the filter settingswere left wide open, i.e., from 0 to 5,000 Hz. Based on a theoreticalevaluation of the signal modality and the factors that are responsiblefor its creation, applicants have found that these signals can berecorded reliably (i.e., without distortion) by using direct current(DC) coupled to amplification.

In the past, no provision has been made for measuring theelectrophysiological activity of a heart in the immediate vicinity inwhich the heart is activated by a pacing catheter. Moreover, if it isdesired to pace the heart at the same time as measuring MAPs in theheart, two entrance sites to the patient must be created and twocatheters must be utilized, which is highly undesirable.

Because of the complexity of electrical cardiac activity, when a pacingelectrode is inserted into the heart, and it is desired to measure theresulting action potentials of the heart, it would be of extremeusefulness to be able to measure such potentials in the vicinity of theactivation, rather than at a more remote location.

Another problem to overcome is the slow DC drift caused by electrodepolarization in conventional electrical material used in the recordingof intracardiac electrical signals, such as silver or platinum. Thesematerials are polarizable and cause offset and drift-which is not aproblem in conventional intracardiac recordings, because those signalsare AC coupled, which eliminates offset and drift. The MAPs, however,are to be recorded in DC fashion, and therefore are susceptible toelectrode polarization. Applicants found that the use of a silver-silverchloride electrode material yields surprisingly good results in terms ofboth long-term stability of the signal and extremely low noise levels.

Another important discovery herein has been that the tip electrode ofthe catheter should be held against the inner surface of the heart withslight and relatively constant pressure. In order to accomplish this ina vigorously beating heart, a spring-steel stylet is inserted into alumen of the catheter of the present invention to act as an elasticcoil, keeping the tip electrode in stable contact pressure with theendocardium throughout the cardiac cycle. This leads to majorimprovements in signal stability.

Thus, a main feature of the catheter of the present invention is tobring into close and steady contact with the inner surface of themyocardial wall a nonpolarizable electrode which both produces andrecords MAPs. To achieve this property, the electrodes are formed fromnonpolarizable material such as silver-silver chloride, and the tipelectrode should be maintained at a relatively constant pressure againstthe myocardial wall, preferably with some type of spring loading. Theendocardial embodiment of the catheter of the present invention containsa spring-steel guide wire which provides this high degree of elasticityor resilience which allows the catheter tip to follow the myocardialwall throughout the heartbeat without losing its contacting force andwithout being dislodged. The inner surface of the heart is lined withcrevices and ridges (called the trabeculae carneae) and are helpful inkeeping the spring-loaded catheter tip in its desired location. Thecontact pressure exerted by the tip electrode against the endocardialwall is strong enough to produce the amount of local myocardialdepolarization required to produce the MAP. The contact pressure is, onthe other hand, soft and gentle enough to avoid damaging the endocardiumor the myocardium or cause other complications. In particular, nocardiac arrhythmias are observed during the application of the catheter.Usually a single extra beat occurs during the initial contact thecatheter tip against the wall, when it is observed. This is a result ofthe stable continuous contact of the tip electrode against the heartmuscle, which is provided by the spring inside the catheter shaft.

It is the tip electrode which is responsible for the generation and therecording of the MAP itself. A reference electrode, required to closethe electrical circuit, is located approximately 3 to 5 mm from the tipelectrode in the catheter shaft and is embedded in the wall so that itis flush with or slightly recessed in the catheter shaft, and makescontact only with the surrounding blood and not with the heart wallitself.

This reference electrode is brought into close proximity with the tipelectrode, since the heart as a whole is a forceful electrical potentialgenerator and these potentials are present everywhere in the cardiaccavities. If the reference electrode were in a remote location, then theamplifier circuit would pick up the QRS complex.

Another design feature important for the purpose of the MAP catheter isto ensure a relatively perpendicular position of the electrode tip withthe endocardial wall. Again, the spring electrode is useful in thisrespect. Conventional catheters are usually brought into contact withthe heart wall in a substantially tangential manner. Such conventionalcatheters are designed simply to record intercardiac electrograms, notMAPs. For the monophasic action potential catheter, direct contact ofbetween the tip electrode and the endocardium is made. This also keepsthe reference electrode, which is located along the catheter shaft, awayfrom the heart muscle.

To facilitate the maneuverability of the catheter during a procedure inthe human heart, the distal end of the catheter should be relativelyflexible during the time of insertion, and the spring-loading featurepreferably comes into action only after a stable position of thecatheter tip has been obtained. Thus, in a preferred embodiment thecatheter is constructed in such a way that the spring wire situated inthe lumen of the catheter is retractable. During catheter insertion, thespring wire or stylet is withdrawn from its distal position byapproximately 5 cm, making the tip relatively soft. Once the catheter ispositioned, the spring wire is again advanced all the way into thecatheter in order to stiffen it and to give it the elastic propertiesthat are important for the described properties.

Important applications of the present invention are in the areas ofdirectly studying the effects of drugs (for example, antiarrhythmiaagents such as procainamide and quinidine) on the heart in real time;studying myocardial ischemia, and in particular, precisely locatingareas of myocardial ischemia by studying localized MAPs; and diagnosingthe nature and locality of arrhythmias originating fromafter-depolarizations. These after-depolarizations have hitherto beendetected only in isolated animal tissue preparations wheremicroelectrodes can be applied. The MAP catheter is a tool that canallow the clinical investigator to detect such abnormal potentials inthe human heart and thereby significantly broaden our ability todiagnose this group of arrhythmias.

A field of study related to the measurement of MAPs is the actual pacingof in vivo hearts to generate such MAPs. A problem with current devicesfor pacing the heart lies in the fact the pacing threshold is relativelyhigh, such that battery life for portable pacemakers is short.

SUMMARY OF THE INVENTION

Therefore, it is an object of the present invention to provide anapparatus for measuring monophasic action potentials.

A further object of the present invention is to provide a MAP measuringapparatus which can accurately record action potentials over sustainedperiods of time.

Another object of the present invention is to provide a MAP measuringapparatus which can measure action potentials on a vigorously beatingin-situ heart.

Another object of the present invention is to provide a MAP measuringapparatus which, with slightly different modifications, may be employedto measure action potentials on both the endocardium and epicardium.

Yet another object of the present invention is to provide a method ofusing the apparatus for recording MAPs.

A further object of the present invention is to provide a method ofdetecting ischemia by sensing MAPs.

In accordance with the above objects, the present invention includes anapparatus for measuring monophasic action potentials in an in vivobeating heart. The apparatus comprises a probe having a tip portion anda first electrode mounted on a terminal end of the tip portion such thata portion of the first electrode is exposed to ambient. A secondelectrode is spaced along the tip portion from the first electrode forsupplying a reference potential signal. The probe is provided withstructure for holding the first electrode in contact with tissue of theheart with a positive pressure without causing significant macroscopicdamage to the heart tissue and for orienting the probe such that thesecond electrode is spaced from the heart tissue.

In accordance with further aspects of the invention, a comparator iscoupled to the first and second electrodes for subtracting signalsreceived through the second electrode from the first electrode. Thecomparator is DC coupled to the electrodes and has a frequency responseof approximately 100 kHz.

The electrodes are non-polarizable, preferably formed of silver-silverchloride, to avoid direct current drift during the course ofinvestigation.

In accordance with further aspects of the invention, a flexible cathetermay be used to hold the tip portion against heart tissue. The secondelectrode is exposed to ambient so as to contact fluid inside the heart.The fluid acts as a volume conductor to establish continuity between thesecond electrode and tissue adjacent that contacted by the firstelectrode. A guide wire, which may be retractable, may be disposed inthe catheter to aid in directing the tip portion. The guide wire in apreferred embodiment has a rectangular or other noncircularcross-section so that resistance to bending in at least one direction ishigher than the resistance to bending in another direction, forassisting in the emplacement and positional stability of the catheter.

In one embodiment, the first electrode is insulated from surroundingelectrically conductive media such as blood by an insulating rim,relative to which the first electrode is recessed.

The probe may also include means for establishing electrical continuitybetween the electrodes and between the second electrode and tissueadjacent the tissue contacted by the first electrode. The continuityestablishing means may comprise saline solution absorbed in foammaterial. The saline soaked foam replaces blood as a volume conductor.

The exposed surface of the first electrode may be approximately 1 mmacross and the two electrodes are separated by a distance ofapproximately 3-5 mm.

The tip portion may also include an insulative material forming a raisedridge around the first electrode exposed portion, and the exposedportion of the first electrode may be generally planar.

In one embodiment, the catheter of the invention is provided with amaterial at the distal end which is more flexible than the material ofthe main body of the catheter. In this embodiment, the stylet may bewithdrawn at least partially from the distal end, so that the cathetermay be inserted past obstructions (such as the tricuspid valve orbranches in the femoral vein) without damage thereto, by allowing thedistal end to flex back upon itself, avoiding vascular perforation orother injury.

One embodiment of the invention includes an S-shaped distal endstiffener, which is advantageous in maintaining the desired force andsubstantially perpendicular position of the catheter against theendocardium.

Another embodiment of the invention provides a combination pacing andMAP catheter for very localized study of the effects of pacing activityon the heart.

In accordance with the invention, a method and apparatus are providedfor determining the force with which the tip electrode of the catheterpresses against the endocardium, wherein the catheter is fixed inposition relative to a gram force gauge, and the distal end is placedinto contact with a lever arm of the gauge, with the resulting forcereading depending upon both the unstressed shape of the distal end andthe stressed shape when the distal end contacts the lever arm. The forcewith which the electrode is actually applied to the in vivo heartstrikes a balance between sufficient local depolarization of themyocardium for a good signal and avoiding damage to the heart tissue.

The method according to the present invention comprises positioning theprobe such that the first electrode is held against heart tissue with apositive force and such that the second electrode is spaced from theheart tissue. The method includes comparing signals from the firstelectrode to reference signals from the second electrode.

According to one alternative to the method of the invention, theelectrodes are short-circuited before contacting heart tissue byimmersing the electrodes in a saline solution.

When the probe includes a flexible catheter, the positioning step of themethod includes percutaneous catheter insertion.

The force applied to hold the first electrode in contact with hearttissue may be on the order of 20 to 50 g over the exposed area of thefirst electrode. A method and apparatus are provided herein whereby suchforce may be accurately determined, by placing the distal end of thecatheter of the invention in a predetermined physical configurationagainst the lever arm of a force gauge.

In a particular embodiment of the present invention, pacing electrodesare provided near the tip of a catheter and are positioned opposite ofone another to form dipole, both features for reducing the potentialthreshold necessary to pace the heart.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other objects of the present invention will become morereadily understood from the following detailed description, referencebeing had to the accompanying drawings in which like reference numeralsrepresent like parts throughout, and wherein:

FIG. 1 is a perspective view of a measuring apparatus of the presentinvention for detecting monophasic action potentials on the surface ofthe epicardium;

FIG. 2 is an elevational sectional view of the tip portion of theapparatus of FIG. 1;

FIG. 3 is a schematic view showing the apparatus of FIG. 1 in operation;

FIG. 4 is a perspective part sectional view showing an apparatus of thepresent invention for measuring monophasic action potentials on thesurface of the endocardium;

FIG. 5 is an enlarged sectional view of the tip portion of the apparatusof FIG. 4;

FIG. 6 is a schematic view showing the apparatus of FIG. 4 in operation;

FIG. 7 is an enlarged view showing an improved tip electrodeconfiguration;

FIG. 8 is an elevational sectional view of the tip electrodeconfiguration of FIG. 7;

FIG. 9 is a schematic diagram showing the circuit connection of theapparatus of the present invention;

FIG. 10A is a graph of time versus millivolts showing actual recordingsof MAPs from a non-ischemic region;

FIG. 10B is a graph of time versus millivolts showing actual recordingsof unipolar DC-coupled electrograms obtained simultaneously with therecordings of FIG. 10A from a nonischemic region;

FIG. 11A is a graph of distance versus millivolts showing unipolar DCelectrograms recorded at indicated distances from the visible border ofcyanosis on hour after induction of ischemia/infarction;

FIG. 11B is a graph of distance versus millivolts showing monophasicaction potentials taken simultaneously with the recordings of FIG. 11A;

FIG. 11C is a graph of distance versus volts per second showing the timederivatives of the monophasic action potentials of FIG. 11B;

FIG. 12 is a graph of millivolts on the left and volts per second on theright versus distance showing mean values of monophasic action potentialamplitudes, maximum derivatives, and total S-T segment voltages acrossthe visible border of cyanosis from 465 recording sites in 7 dogs;

FIG. 13A is a graph of distance versus millivolts showing the effect ofthe duration of ischemia on S-T segment voltages recorded across avisible cyanotic border at intervals of 1 hour and 3 hours;

FIG. 13B is a graph of distance versus millivolts showing the effect ofthe duration of ischemia on monophasic action potential amplitudes atintervals of 1 hour and 3 hours; and

FIG. 13C is a graph showing distance versus volts per second showing theeffect of the duration of ischemia on maximum derivatives at intervalsof 1 hour and 3 hours;

FIG. 14 is an isometric view of another embodiment of the invention;

FIG. 15 is an enlarged cross-sectional view of the distal end of theapparatus as enclosed by the arc 15--15 in FIG. 14;

FIG. 16 is an enlarged cross-sectional view of an intermediate portionof the apparatus as enclosed by the arc 16--16 in FIG. 14;

FIG. 17 is a perspective view of another embodiment of the presentinvention;

FIG. 17A an enlarged view of an alternative embodiment of the distal endof the apparatus of FIG. 17;

FIG. 18 is a perspective view of an alternative distal end for thecatheter of the invention;

FIG. 19 is a sectional view taken along line 19--19 of FIG. 18;

FIG. 20 is a sectional view taken along line 20--20 of FIG. 18;

FIG. 21 is a perspective view, partly in section, of an alternativeembodiment to the distal end of the catheter of the invention;

FIG. 22 is a view showing the catheter of FIG. 21 in use;

FIG. 23 is another view showing the catheter of FIG. 21 in use; and

FIG. 24 is a diagram showing the method and apparatus for determiningthe force exerted by the distal end of the catheter of the invention.

FIG. 25 shows an alternative embodiment of the device of FIG. 17.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIGS. 1 and 3 show a probe 10 according to the present invention. Probe10 comprises a tip portion 12 which is connected to an end of arelatively stiff, flexible wire 14. The end of wire 14 attached to tip12 is L-shaped. Wire 14 is also bent into two loops to form a springsection 16 and the opposite end of wire 14 attaches to a connector 18. Apair of electrical leads 20 and 22 are wrapped around wire 14. Leads 20and 22 extend from the tip portion 12 to connector 18 and attach toterminals in connector 18. Connector 18 is a conventional electricalconnector for making contact with leads extending to amplification anddisplay circuitry, to be discussed hereinafter.

The portions of wire 14 above and below spring 16 are encased in plasticsheathing sections 24 and 26, respectively. Sheathing sections 24 and 26are shown in sectional view only in FIG. 1.

Wire 14 can be conventional stainless spring steel wire which, combinedwith spring section 16, can produce a consistent force of approximately20 to 30 g at the tip portion 12 when the tip portion is held against arapidly beating in vivo heart. Sheathing 26 can be Teflon tubing or thelike, and connector 18 is a conventional electrical connector whichreceives leads 20 and 22.

FIG. 2 shows tip portion 12 in greater detail. Wire 14 terminates partway into the tip portion. Sheathing 14 is filled with epoxy resin 30beyond the termination of wire 14. The epoxy resin is firmly attached towire 14 and to the sheathing. A tip electrode 32 is embedded in theepoxy resin 30 at the extreme terminus of the tip portion 12. Electrode32 is a silver-silver chloride pellet which protrudes to form a smoothspherical surface approximately 1 mm in diameter. A proximal electrode34 is also embedded in the epoxy resin 30 a distance of approximately3-5 mm from the tip electrode 32 along tip portion 12. Proximalelectrode 32 is also a silver-silver chloride pellet approximately 1 mmin diameter. Proximal electrode 32 is accessible through an opening 35in sheathing 26. Electrodes 32 and 34 comprise a nonpolarizable matrixof silver-silver chloride. These electrodes are available in 1 mmpellets from In Vivo Metric Systems of California under the part no.E205.

Electrical wires 20 and 22 are connected, respectively, to electrodes 32and 34 so as to provide electrical continuity between the electrodes andthe terminals in connector 18.

Sheathing 26 is covered with a layer of foam rubber 36 which extendsfrom above electrode 34 to a level approximately equal to electrode 32.The foam rubber is substantially cylindrically shaped and soaked with a0.9% saline solution. The primary purpose of the foam rubber is tosuspend the saline solution so as to provide electrical conductivitybetween proximal electrode 34 and tissue adjacent that which iscontacted by tip electrode 32, as will be discussed hereinafter.

Now, with reference to FIGS. 2 and 3, an example ;of the use of probe 10will be discussed.

Mongrel dogs weighing 20 to 30 kg were anaesthetized by intravenousinjection of sodium pentobarbital (25 mg/kg) or chloralose (60 mg/kg).Respiration was maintained with room air through a cuffed entotrachealtube by a Harvard respirator. The heart was exposed through leftthoractomy and suspended in a pericardial cradle.

Probe 10 was positioned against the epicardium 40 such that tipelectrode 32 contacted the epicardium with a force of approximately20-30 g while the heart beat. The force was maintained by the springsteel wire 14 and spring 16 formed in wire 14.

Epicardial MAP recordings were obtained by DC coupling the tip andproximal electrodes to a differential preamplifier 42, as shown in FIG.9, with an input impedance of approximately 10¹¹ ohms and a frequencyrange from direct current to 100 kHz. It should be noted that apreamplifier having a frequency range of direct current to approximately5000 Hz should be sufficient for this application. The preamplifiedsignal was displayed on a Tektronix storage oscilloscope 44 and writtenout on a multichannel photographic recorder 46.

The probe 10, either mounted or hand held, provided continuous MAPrecordings of stable amplitude, smooth contour, and isopotentialdiastolic baselines over prolonged time periods from a single epicardialsite. FIG. 10A shows an example of the epicardial MAP recordings. Thearrow indicates the time at which contact pressure was applied. FIG. 10Bshows the corresponding epicardial unipolar electrograms recorded byconnecting the proximal electrode 34 of probe 10 to a second DC-coupledamplifier 42' (FIG. 9) and connecting a distant reference electrode 50(FIG. 3) to the negative input of amplifier 42'. In FIGS. 10A and 10B,the first half of each graph was recorded at a speed of 10 mm/sec andthe second half at a speed of 50 mm/sec.

The distant reference electrode 50 was provided by another silver-silverchloride electrode sewn into the aortic root. The stability of theO-reference potential of the MAP recordings was checked at the beginningof each experiment and between interventions by comparing it with thediastolic potential recorded at the aortic root.

The exact mechanism underlying the genesis of the contact electrode MAPis not clearly understood. It is theorized that the MAP recordings wereobtained by exerting pressure with the tip electrode 32 against a smallregion of epicardium 40. This likely depolarizes a number of myocardialcells such that they are no longer capable of participating actively inregenerative depolarization and repolarization. The magnitude anddirection of local current flow, which results from the potentialdifference between the depolarized cells under the tip electrode 32 andthe adjacent normal cells would determine the amplitude and polarity ofthe extracellular MAP recording. The magnitude of current flow, however,may not only depend on the difference in membrane potential betweencells subjacent and adjacent the electrode tip. Other factors, such asthe number of cells depolarized and therefore involved in generatingcurrent flow, the degree of electrotonic coupling of cells at theboundary of interest, and the conductance in the extra- andintracellular media surrounding the recording sight are likely toinfluence extracellular current flow and the amplitude of the MAP.

Referring again to FIG. 2, it should be understood that the purpose ofthe saline soaked foam rubber 36 is to provide a conductive path betweenproximal electrode 34 and the epicardium 40 surrounding tip electrode32. In other words, the foam rubber acts as an extension of proximalelectrode 34 but does not pressurize the epicardium and thus does notcause depolarization of the myocardium. The actual potential beingmeasured appears to be that between the depolarized myocardium directlybeneath the tip electrode 32 and the surrounding tissue.

FIG. 4 shows a catheter 60 used for bipolar measurements of MAPs fromendocardial sites. Catheter 60 has a tip portion 64 which is shown ingreater detail in FIG. 5. Tip portion 64 contains a tip electrode 72 anda proximal electrode 74. Catheter 60 comprises flexible tubing 62 whichmay be Teflon or other durable material having a memory. Tubing 62 mustbe sufficiently flexible to be easily bent by the action of a beatingheart, yet sufficiently resilient to maintain the tip portion 64 of thecatheter in contact with the endocardium with a force estimated atapproximately 20-30 g. A stainless steel guide wire 66 is inserted inthe tubing 62 to improve the resiliency of the tubing and to aid inpositioning the catheter tip portion 64. A pair of electrical leads 68and 70 also extend through tubing 62 to make contact with tip electrode72 and proximal electrode 74, respectively. The opposite ends ofelectrical leads 68 and 70 are connected to electrical connectors 76 and78, respectively.

As shown in FIG. 5, tip 64 is similar to tip 12 of probe 10 except thatno foam rubber is provided around the tip. Tip electrode 72, which is asintered silver-silver chloride pellet of approximately 1 mm diameter,the same as tip electrode 32, protrudes from the terminal end of tipportion 64. Electrode 72 is held in place by epoxy cement 80, orpreferably by cyanoacrylate adhesive, which has been determined to berelatively inert and biocompatible. A silver wire 82 extends from tipelectrode 72 and is soldered at point 84 to insulated lead 68.Similarly, proximal electrode 74, which is spaced about 5 mm upwardlyalong the tip portion 64 from electrode 72, is fixed in position byepoxy 80 and is connected to a silver wire 86 which is soldered at point88 to insulated lead 70. The proximal electrode 74 is accessible throughan opening 90 in tube 62 and is recessed somewhat within the catheter sothat contact is made only with the outer medium (blood) in the heart andnot the endocardium.

The tip and proximal electrodes of catheter 60 are connected to apreamplifier 42 (FIG. 9) through connectors 76 and 78 to provideoscilloscope and recorded readouts of the MAPs. A remote electrode canbe placed in subcutaneous tissue remote from the heat, that is, at thesite of catheter insertion, to provide intracavitary electrograms.

Catheters have been employed having lengths from approximately 100-150cm and a total outside diameter of approximately 1.3 cm. The springsteel guide wire may have a diameter of approximately 0.012-0.013inches.

An example of the use of catheter 60 will now be set forth.

Before catheterization, electrodes 72 and 74 were immersed in sterile0.9% saline solution for one hour with leads short-circuited to balancehalf-cell potentials. This procedure ensured that no appreciable directcurrent drift occurred during the course of the investigation. Diastolicbaseline of intracavitary electrograms usually remain stable within % 1mV during the entire recording time (1-3 hours). It should be noted thatstainless steel or platinum electrodes conventionally used in clinicalelectrophysiology may produce considerable baseline drift of up to 160mV during the first 30 minutes. After percutaneous catheter insertion bySeldinger technique and fluoroscopic positioning of the catheter withinthe heart, electrode leads were connected with sterile cables to thedifferential preamplifier 42. Firm approximation of the tip electrode tothe endocardial surface was indicated by the recording of monophasicaction potentials, which stabilized in amplitude and duration over a fewbeats.

FIG. 6 depicts the catheter 60 measuring MAPs at several differentventricular sites in a heart. The various sites are numbered 1 through 6in FIG. 6. In each instance, positioning of the tip portion of thecatheter was under fluoroscopic control.

FIG. 7 and 8 show an alternate embodiment of a tip electrode 90 whichcan be used to replace either tip electrode 32 in probe 10 or tipelectrode 72 in catheter 60. Tip electrode 90 is again sinteredsilver-silver chloride with an exposed surface diameter of approximately1 mm. However, the exposed surface 92 is substantially planar and issurrounded by a small ridge 94 of insulating material. This tip designhas proven to be most effective in producing long-term stable recordingsof monophasic action potentials. The ridge 94 aids in sealing offcontact of electrode 90 from the adjacent tissue and fluid. The design othe reference electrode is as before, i.e., it is mounted along theshaft 3-5 mm proximal from the tip.

The depth ridge 94 should only be approximately 0.1 mm. The purpose ofridge 94 is to seal off electrode 90 from the surrounding tissue but notto prevent the electrode from pressurizing the myocardium. electrode 90must both produce the pressure and sense the voltage in the pressurizedtissue. If the height of ridge 94 is too great, electrode 90 will beprevented from producing adequate pressure.

Ridge 94 creates a high resistance between the pressed tissue and thesurrounding tissue. The thickness of ridge 94 should also not be toogreat so that the electrode is close to the boundary created by theridge.

Referring again to FIG. 1 and 4, it will be appreciated that the primarydifference between probe 10 and catheter 60 is that probe 10 includes asaline soaked foam rubber piece 36. In probe 10, the saline solutionacts as a volume conductor which establishes electrical continuitybetween the proximal electrode and the tissue surrounding the tissuepressed by tip electrode 32. With the catheter 60, the fluid (blood)within the heart itself is the volume conductor which serves thispurpose. Therefore, no additional conductive material is required.

It should also be appreciated that with prior known suction electrodecatheters, focal hemorrhage results at the site of suction within a fewminutes. In contrast, no macroscopic damage to the tissue was seen instudies with the continuous contact electrode of the present invention.Furthermore, the stability of the contact electrode MAP over longrecording periods may be considered indirect evidence that cellularalterations that lead to electrical uncoupling were minimal.

Thus, MAP recordings using the present invention appear to be safe andcan easily be performed during routine cardiac catheterization alongwith other electrophysiologic measurements and pharmacologicinterventions. MAPs recorded with the present invention can also providea sensitive index of acute myocardial ischemia.

Identification of Ischemia/Infarction Using Monophasic Action Potentials

The ability to localize a region of myocardial ischemia by epicardialMAP recordings has been examined in 8 dogs and compared with standardepicardial S-T segment mapping. In order to produce transmural ischemiaand infarction in a canine heart, the left anterior descending coronaryartery (LAD) was permanently ligated proximal to the first diagonalbranch and a biologically inert, non-resorbable polymer (dental rubber)injected into the arterial lumen. The ligation is shown on FIG. 3 at100. This technique of vascular embolization, which extends into thearterioles, has previously been shown to create transmural infarcts withsharp histological borders in canine hearts. The white color of theinjectate was also helpful in determining the vascular distribution ofthe LAD. Prior to ligation, 6 to 8 control measurements of theepicardial MAP and unipolar electrograms were made from definedlocations inside and outside the anticipated ischemic region. Epicardialmapping was begun one hour after LAD occlusion and embolization and wascompleted within 15 minutes. The hand-held recording probe 10 wasconsecutively placed at multiple sites within, outside and near theborder of the area of visible cyanosis. In each dog, measurements weremade from 45 to 645 sites with an increased frequency of recordingsclose to the visible cyanotic border (shown in FIG. 3). The distance ofthe recording sites to the visible border of cyanosis was measured witha flexible ruler and recorded spatially on as map of the epicardialsurface. For graphic presentation of mean data, the amplitude and dV/dtmax of the MAP and the total S-T segment voltage (T-Q depression plus"true" S-T elevation) were averaged in 2 mm intervals inside and outsidethe visible cyanotic border. These data are shown in FIG. 12, to bediscussed hereinafter.

In order to assess the effect of duration of ischemia on theelectrocardiographic measurements, epicardial mapping was repeated in 2dogs, 3 hours after coronary artery ligation and embolization, atlocations similar to the mapping study performed at one hour. The dataobtained are shown in FIG. 13, also to be discussed hereinafter.

In FIG. 10 are shown examples of MAP recordings (A) and standardunipolar electrograms (B) obtained from the epicardial surface of thecanine left ventricle prior to ischemia. In general, MAP signalsdemonstrated "full" amplitude within 5 to 10 beats after stable contactof the electrode with the myocardial surface had been established. Thetime of contact is shown by the arrow in FIG. 10. Thereafter, MAPrecordings remained stable in amplitude, dV/dt_(max) and configurationfor continuous recording periods of 1 hour or more. Usingnon-polarizable silver-silver chloride electrodes and DC amplification,it was possible to demonstrate a negative diastolic potential and apositive systolic potential with respect to the zero reference obtainedfrom the diastolic baseline of the epicardial surface recording measuredprior to application of significant contact pressure. Total amplitude ofcontrol MAPs recorded from the left ventricular epicardial surfaceranged from 35 to 55 mV (42% 4 mV, means % S.D.) which is considerablysmaller than amplitudes previously reported for transmembrane actionpotentials (120 mV). In addition, the ratio of the positive voltage("overshoot" ) to the total amplitude was greater in MAP than inintracellular recordings. The total MAP duration measured at 90%repolarization (MAPD30) was 144% 12 msec measured at a constantspontaneous heart rate of 120 % 5/min. Similar durations have beenreported for transmembrane actio potentials of canine ventricularmyocardium.

To further examine the precision of MAP recordings for localizingregional myocardial ischemia, epicardial MAP recordings were made withthe hand-held probe 10 across the border of the regions which was madetransmurally ischemic by coronary artery ligation and distalembolization with dental rubber, as discussed above. FIG. 11 showsoriginal MAP recordings (B), their first time derivative (dV/dt) (C) andadjacent, simultaneously recorded unipolar epicardial electrograms (A)at various distances from the cyanotic border one hour after inductionof transmural ischemia/infarction. MAPs recorded 20 nm or more outsidethe visible border of cyanosis had amplitudes, durations, configurationsand dV/dt_(max) values comparable to those recorded at distant sites andcomparable to those recorded at the same site prior to occlusion.Epicardial MAPs recorded from sites 10 mm or less outside the cyanoticborder demonstrated noticeable decreases in plateau amplitude andduration and decreases in the slope of the final repolarization phase(phase 3), resulting in a more triangular shaped MAP with a greatertotal duration. Values of dV/dt_(max) were also noted to be decreased atthese sites. As the MAP recording probe was moved across the cyanoticborder, MAP amplitude decreases sharply and dV/dt_(max) valuesapproached zero 2 mm inside the border. The decrease in MAP amplitudewas due to a loss in both diastolic (negative) and systolic (positive)potential. In the center of the ischemic region, nearly isopotentialrecordings at negative potentials ranging from -15 to -5 mV wereobtained. In contrast, epicardial S-T segment voltages were highest justinside the cyanotic border decreasing progressively toward the center ofthe ischemic region. As seen in FIG. 11A, these increases in total S-Tsegment voltage were due to a combination of "true" S-T elevation andT-Q segment depression. The relative contribution of T-Q segmentdepression, however, was greater in recordings inside the ischemicregion (where MAP recordings demonstrated markedly reduced diastolicpotentials). In contrast, outside the cyanotic border, true S-T segmentelevation contributed the largest portion of the total S-T segmentchange.

In FIG. 12 are summarized MAP and total S-T segment recordings made in 8dogs across the lateral border of cyanosis 1 hour after induction oftransmural ischemia. Unipolar epicardial electrograms demonstratingsignificant S-T segment elevations (27% 6 mV) were recorded 4 mm insidethe cyanotic border. In epicardial electrograms recorded near the centerof the ischemic region, both T-Q and S-T segment displacements werefound to be lower in magnitude than those recorded just inside theborder. Total S-T segment voltages in these more central ischemicregions (16-22 mV) were not significantly different in magnitude fromthose measured 4-6 mm outside the border (p. 13). Unipolar electrogramsrecorded in the center of the ischemic region did differ from thoserecorded just outside the border, however, by the presence of diminishedR wave voltage and/or the presence of Q waves (FIG. 11). In particular,in FIG. 12, the uniform loss in MAP amplitude and dV/dt throughout theischemic region should be noted. This is in contrast to the decline inS-T segment voltage towards the center of the ischemic region.

The distribution of blood flow across the lateral border of the cyanoticregion was determined in 6 dogs using the radioactive microspheretechnique. Myocardial blood flow was 1.42% 0.35 ml/min/g in thesubepicardial layers and 0.65% 0.28 in the subendocardial layers 2-4 mmoutside the visible edge of cyanosis and decreased to 0.01% 0.05 and0.01% 0.02 2-4 mm inside the cyanotic border. These flow data confirmthat the technique used to produce transmural infarction in a canineheart resulted in a sharp lateral border of ischemia with a transitionfrom normal to zero blood flow over a width of only 6 mm.

The influence of the duration of ischemia on the transition of MAP andcorresponding S-T segment recordings across the cyanotic border wasstudied in 3 additional dogs. These results are shown in FIG. 13.Measurements of MAP amplitude and dV/dt_(max) repeated 2 hours after theinitial mapping study demonstrated near zero values even closer to theedge of the cyanotic border than after 1 hour of ischemia as well asfurther reductions just outside the border. In contrast, epicardial S-Tsegment elevations demonstrated an overall decrease in magnitude overthe same time period, making localization of the border even less welldefined.

The local epicardial S-T segment voltages recorded using probe 10 areconsistent with previous reports of the ability of epicardial S-Tsegment mapping to delineate a region of ischemia. S-T segmentelevations were found 20- mm or more outside the cyanotic border andreached maximum values just inside the border. As also demonstrated inprevious studies, S-T segment voltages decreased towards the center ofthe ischemic area such that the magnitude of S-T segment elevationsrecorded in the central ischemic regions was not significantly differentfrom those recorded at sites 5 to 10 mm outside the area of reducedflow. The wide zone of transition of epicardial S-T segment voltageacross the border and the loss of S-T segment voltage in the center ofthe ischemic region are expected on theoretical grounds. S-T segmentdisplacements are caused by current flow between normal and ischemicmyocardium. Potential gradients and thus injury current flow are lessbetween adjacent ischemic regions than between ischemic and normalregions resulting in greater S-T segment voltages closer to the ischemicborder than in the center of the ischemic area. In contrast, loss ofepicardial MAP amplitude and dV/dt_(max) were found to be uniformthroughout the ischemic region, thus correlating better with the absenceof flow.

The transition from nearly absent to nearly normal MAP recordings acrossthe cyanotic border occurred over a distance of less than 8 mm. Thiselectrical transition was slightly greater in width than the flowtransition which had a width of approximately 6 mm. The width of theborder "zone" over which transition in flow, metabolism orelectrophysiologic variables are detected depends on the resolving powerof the techniques employed to measure these variables. The finding ofintermediate values for flow, metabolites or electrophysiologicalchanges could result from measurements obtained either from a mixture ofnormal and ischemic cells or from a uniform composition of cells with anintermediate degree of change. The slightly wider transition for MAPchanges, as compared to the flow transition, may indicate a limit to theresolving power of MAP recordings or may reflect scatter related tomicrosphere flow measurements being made from 12 mm wide tissue samples.On the other hand, abnormal MAPs recorded just outside the cyanoticborder do not necessarily indicate that the tissue recorded from isinjured. Current flow between ischemic and nonischemic tissue maydecrease the amplitude and rise velocity of transmembrane actionpotentials in nonischemic cells.

A decrease in the magnitude of S-T segment voltages with duration ofischemia (see FIG. 13) has been documented in both experimental andclinical studies. It has been reported that epicardial and intramuralS-T segment potentials in the porcine heart reach maximal values 7 to 15minutes after coronary artery ligation and then decrease with timedespite a progressive deterioration of the metabolic situation.Substantial reduction in S-T segment elevation in patients over thefirst 24 hours following acute myocardial infarction has been reportedas part of the natural history of myocardial infarction. Thisdiscrepancy between S-T segment voltage and metabolic and histologicdeterioration has been explained by progressive electrical uncouplingbetween damaged and normal myocardial cells so that, despite apersistent electrical gradient, flow of injury current decays andeventually ceases. In contrast, ischemia-induced loss of MAP amplitudeand dV/dt_(max) persists or becomes even more pronounced three hoursafter coronary artery occlusion and distal embolization than after onehour. This indicates that the information on ischemic injury obtainedfrom MAP recordings is not compromised by electrical uncoupling as isthe ECG, and suggest that MAP recordings can be used not only as a moreprecise but also more reliable electrophysiologic index for defining thespatial extent of ischemic/infarcted myocardium.

In general, the apparatus and method of the present invention can beused to detect ionic imbalance due to a change in electrolyte balance inthe heart as well as ischemia due to a reduction in blood flow.

Monophasic action potentials (MAPs) have hitherto mostly been recordedwith suction electrodes. However, the "contact electrode" technique ofthe present inventio provides more stable MAP recordings than suctionelectrodes and has been shown to also allow safe, long-term MAPrecordings in human subjects without tissue injury. Endocardial andepicardial MAP recordings using the present invention have been found toresemble transmembrane action potentials and, following the induction ofregional ischemia or changes in potassium ion concentration, undergochanges similar to those previously reported in intracellularrecordings. Localization of a region of myocardial ischemia by MAPmapping is more accurate and less dependent on the duration of theischemic process than S-T segment mapping. Endocardial MAP mapping inthe cardiac catheterization laboratory and both epicardial andendocardial MAP mapping in the cardiac operating room should permit theidentification of sites of regional ischemia in man and to assess theacute effect of therapeutic interventions designed to reduce theseverity of an ischemic insult.

In FIGS. 14, 15 and 16 there is shown another embodiment of theapparatus of the present invention for measuring monophasic actionpotentials in an in vivo beating heart which also can be described as anintracardiac contact electrode catheter 101 which also can be identifiedas a probe. The catheter 101 consists of a flexible elongate element 102which is provided with proximal and distal extremities 103 and 104. Theflexible elongate element 102 consists of an outer jacket or body 106and an inner jacket or body 107. The outer jacket 106 and the innerjacket 107 can be formed of a suitable material as, for example, theycan be formed of heat shrinkable plastic such as polyethylene. The innerjacket 107 extends over a structural reinforcing tube 108 which can bein the form of 23 gauge hypodermic needle stock formed of a suitablematerial such as stainless steel. The tube 108 extends from the proximalextremity 103 of the catheter 101 into a region near the distalextremity 104 of the catheter 101 as, for example, within eightcentimeters of the distal extremity 104. Thus, by way of example for acatheter 101 of approximately 100 centimeters in length, the tube 108can have a length of approximately 92 centimeters and would extend to anintermediate portion 109 as shown in FIG. 14 and 16.

An additional stiffener element 111 extends from the distal extremity104 of the catheter as shown particularly in FIG. 15 and into the distalextremity of the tube 108. The stiffener element 111 can also be formedof a suitable material such as tempered stainless steel wire having adiameter of approximately 0.016 inches. It can extend from the distalextremity 104 as shown in FIG. 15 into a bore 112 provided in the tube108 and can extend substantially the entire length of the catheter. Thetapering of the element 111 provides a graduation in the flexibilitythereof, such that the distal end of the element 111 is much moreflexible than the proximal end. The tapered portion of the element 111may be contained entirely within the S-shaped portion 156, so that theelement 111 is of substantially constant diameter between its proximalend and the portion 156. It should be appreciated that the additionalstiffener element 111 can be eliminated where the additional stiffnessis not necessary.

A cylindrical electrode housing 121 is provided on the distal extremityof the inner jacket 107 and has its proximal extremity mated with thedistal extremity of the inner jacket 106 and is secured thereto bysuitable means such as an adhesive. To facilitate the making of a goodbond between the housing 121 and the outer jacket 106, an annular recess122 is provided in the distal extremity of the outer jacket 106 and anannular recess 123 is provided in the housing 121 which receive a sleeve127 formed of a suitable material such as a polycarbonate and bondedtherein by a suitable adhesive.

An ovoid recess 128 is formed in the housing 121 and is approximately0.064 inches in length, and 0.046 inches in width. The distal extremityof the housing 121 is provided with an annular recess 129 which receivesthe proximal extremity of a cylindrical tip retainer 131 formed of asuitable material such as a polycarbonate and retained therein bysuitable means such as an adhesive. A forwardly facing opening 132 isprovided in the retainer 131. A conical type wedge 133 having a head 134is seated in the bore 112 and expands the distal extremity of the innerjacket 107 so that it tightly engages the tip retainer 131 to provide apress fit.

The retainer 131 preferably includes a rim 131a which defines theopening 132 and protrudes slightly beyond the edge of the tip electrode139. With this design, when the tip electrode is in place against anendocardial site, the rim 131a contacts the endocardium surrounding thesite, and so prevents the tip electrode 139 from making electricalcontact with blood within the heart. As can be seen, the side electrode141 is thus dimensioned so that it is slightly recessed within therecess 128 so that the outer periphery of the side electrode 141 issurrounded by the insulating material of the rim 131a which can providea seal between the side electrode 141 and the blood. This ensures thatthe tip electrode is electrically isolated from the side electrode 141,which produces accurate and reliable MAP readings.

A pair of electrical conductors 136 and 137 which can be formed of asuitable material such as insulated copper are provided which serve assignal wires. The conductors 136 and 137 are provided with S-shapedterminal portions 136a and 137a respectively which are embedded in asuitable conducting material to form electrical contact therewith toprovide a tip electrode 139 and a side electrode 141. It has been foundto be preferable to form the tip and side electrodes 139 and 141 byutilizing a silver-based conductive epoxy or other binder and adding tothat approximately 20% by weight silver-silver chloride which has beenfound to provide a stable offset potential for a period in excess of oneor two hours.

A particularly suitable structure for the electrodes 139 and 141 isprovided by utilizing silver-silver chloride flakes (rather than powder)bound together by cyanoacrylate adhesive. This will produce aparticularly conductive electrode, and the cyanoacrylate is a relativelyinert and strong binder which is biocompatible.

It has been found such an electrode matrix has been particularlysatisfactory in that it makes it relatively easy to manufacture the tipelectrodes. After the tip electrodes are in place, they are machined tothe desired conformation, for example, the convex shape for the sideelectrode 141. It is believed that this machining is also advantageousbecause in addition to shaping the electrode it exposes thesilver-silver chloride crystals so that they come in direct contact withthe heart during use of the apparatus or device as hereinafterdescribed. The material can be molded and pressed around the S-shapedtips 136a and 137a of the conductors 136 and 137 thereafter permittingthe conductive binder to harden in place. It has been found that it isdesirable to place the side electrode 141 proximal of the tip electrode139 by a suitable distance as, for example, 3 to 5 millimeters.

The conductors 136 and 137 are connected at their proximal extremitiesto conductive flexible insulated leads 148 and 149 that terminate inadaptors 151 and 152 respectively. A sleeve 153 formed of a suitablematerial such as a heat shrinkable plastic is mounted on the proximalextremity 103 of the catheter 101 and encapsulates the connections made(not shown) between the leads 148 and 149 and the conductors 136 and137.

As can be seen particularly in FIG. 14, a gentle S-shaped bend orcurvature 156 is provided in the proximal extremity of the catheter 101which serves to provide the springiness desired to maintain the tipelectrode 139 in contact with the heart muscle during the time that theheart is beating. As explained in connection with the previousembodiments, it is desirable that the catheter electrode housing 121 bedisposed in a direction which is substantially perpendicular to thepoint at which the catheter engages the heart muscle which permits thetip electrode 139 to engage the surface of the heart and to leave theside electrode 146 free in the blood medium. This ensures that therewill be no short circuit between the electrodes except through the bloodwhich serves as the conducting medium. The S-shaped curvature 156 isimportant in that it facilitates proper alignment of the distalextremity of the catheter 101 with the heart so that theperpendicularity hereinbefore described is obtained. In addition, theS-shaped bend 156 provides a certain amount of resilience that ensuresthat a substantially constant contact pressure is provided against theendocardium while the heart beats.

Thus, it can be seen that with the present invention a catheter has beenprovided which can be pressed against the heart with a force andposition which remain substantially constant even while the heart isbeating. The S-shaped bend is like an elastic spring to accommodate themovement of the beating heart while at the same time maintaining asubstantially constant pressure on the heart so that accurate andprecise signals can be obtained by the electrodes to make it possible torecord stable signals over relatively long periods of time as, forexample, one to two hours.

FIG. 17 shows an alternative embodiment of the invention, depicting acatheter 200 which is a combination pacing catheter and MAP catheter.Thus, the new combination catheter 200 has been arrived at, in whichpacing electrodes 210 and 220 are mounted at the distal end 230 of thecatheter 200. In addition, a tip electrode 240 and a side electrode 250are provided, as in the configuration of FIG. 5, and are electricallyconnected to connections such as plugs 260 and 270, respectively.

The pacing electrodes 210 and 220 are similarly connected to plugs 280and 290, respectively. Plugs 280 and 290 are standard plugs. The methodof use of pacing electrodes such as electrodes 210 and 220 foractivating is well known in the art in standard configurations pacingelectrode catheters; that is, the same types of electrical signals whichare provided to pacing electrodes in standard pacing catheters may alsobe provided to the electrodes 210 and 220 in the present invention. Itwill be understood that contained within FIG. 17 are the necessaryelectrical leads to the electrodes 210, 220, 240 and 250, and inaddition stylets and other features as described herein with respect toother embodiments may be included.

A coupling 300 for the plugs 260-290 is provided, insuring a reliableconnection between the plugs to the electrical leads contained withinthe catheter 200. This coupling 300 is preferably of a hard materialsuch as polycarbonate, and has an enlarged diameter relative to thecatheter 200. This provides greater torque control for the user of thecatheter when manipulating the catheter into the heart and positioningthe tip electrode 240 against the endocardium.

In addition to the coupling 300, a knurled knob 310 may be attached atthe proximal end 320 of the catheter 200. The knob 310 is preferablyconnected to the catheter 200 in a nonrotatable fashion, such that axialrotation of the knob 310 causes similar axial rotation of the catheter200. As shown in FIG. 17, the knob 310 may be generally cylindrical inconfiguration, or may be of some other convenient shape for twisting byhand.

In the preferred embodiment, the electrode 210 is located 2-6 mm fromthe tip 230. The other electrode 220 is also located 2-6 mm from the tip240. As shown in the preferred embodiment, the distances between the tip240 and the electrode 210 is substantially equal to the distance betweenthe electrode 220 and the tip 240. Also, in the preferred embodiment,the electrodes 210/220 range in size from about 1-3 mm.

An alternative embodiment for the distal end 230 of the catheter 200 isshown as distal end 235 in FIG. 17A. In this embodiment, two pacingelectrodes (which are typically made from platinum) 215 and 225 areprovided, with the pacing electrode 215 being disposed at the tip 245 ofthe distal end 235. In this embodiment, the tip electrode 255 is reducedin size (relative to the tip electrode 240), but the side electrode 255is the same as in the configuration shown in FIG. 17. As with the FIG.17 embodiment, each of the electrodes 215, 225, 255, and 265 shown inFIG. 17A includes its own electrical connection to a plug at theproximal end of the catheter.

A distinct advantage of the configuration of FIG. 17A is that the pacingelectrode 215 is positioned directly adjacent the tip electrode 255. Asmentioned above, devices presently available are unable to providepacing in the immediate vicinity of action potential measuring, and boththe configurations of FIG. 17 and FIG. 17A for the first time providesuch capability. In FIG. 17, the pacing electrodes 210 and 220 arepreferably disposed as close to the tip electrode 240 as possible, withthe configuration of FIG. 17A allowing the electrodes 215 and 255 to beextremely close, separated only by a layer of insulation 285, such aswould separate two lumens in a catheter. Thus, pacing may be provided inthe same area of myocardium as action potential measurement, providing anew and heretofore unavailable method of measuring the heart's reactionto pacemaking.

One particularly useful advantage to the combination pacing/MAP catheteris in determining the effective refractory period of the heart, i.e. thelongest interval between two separate stimuli to the heart where thesecond stimulus fails to energize the heart. In other words, theeffective refractory period is the time required by the heart to recoverfrom the effects of depolarization. There is a correlation between theeffective refractory period (which may be on the order of 250 ms) andthe action potential, and both of these may vary significantly from siteto site within the heart. Thus, an important application of thecombination catheter 200 is to detect the correlation between theeffective refractory period and the MAPs generated for specificlocations in the heart. Such an application is described in detail inthe article by M. Franz (one of applicants herein) and A. Costardentitled "Frequency-dependent effects of quinidine on the relationshipbetween action potential duration and refractoriness in the canine heartin situ," Circulation 77, No. 5, 1177-1184, 1988, which is incorporatedherein by reference. It will be noted that this article describes such amethod utilizing two electrodes; however, the embodiment of the currentinvention involving four electrodes (as in FIGS. 17 and 17A) alsoenables the use of such a method, and it is advantageous to useseparate, slightly spaced, electrodes for the pacing electrodes and theMAP electrodes, respectively.

Another alternative embodiment to the invention is shown in FIGS. 18-20.In this embodiment, a catheter 330 is provided of a configurationsimilar to that described with respect to the other embodiments herein,including a tip electrode 340 with its electrical connection 350, and aside electrode 360 with its electrical connection 370. The catheter 330is formed from two different materials, with a main section 380 formedfrom a relatively stiff material such as polyurethane, and a tip section390 formed from a softer material, such as the PELLETHANE 2363-80A(trademark) polyurethane product produced by Dow Chemical.

The tip portion 390 is preferably of a substantially solidcross-section, as shown in FIG. 19, with three lumens 400,410 and 420there through. As shown in FIG. 19, lumens 400 and 420 are generallycircular in cross-section to accommodate the electrical connections orleads 350 and 370. Other cross-sectional shapes for the lumen 400 and420 are acceptable, so long as they accommodate the cross-sectionalshapes of the connections 350 and 370.

The lumen 410 is noncircular in cross-sections, and in the preferredembodiment is substantially rectangular. An elastic stiffener 430 isprovided, and extends through the lumen 410 from the distal end of thetip section 390 to the main section 380. The elastic 430 may comprise ametal ribbon or other material which may be permanently bent into adesired configuration and have the characteristics of elasticity ofspringiness, so that when the distal end 440 of the catheter 320 ispressed upon slightly, the ribbon 430 will bend, but will spring back toits original shape upon release. However, more substantial pressure onthe distal end 440 i.e., bending the ribbon 430 such that the arcdescribed between its first end 450 and its second end 460 changessubstantially, will cause the ribbon 430 to deform into a differentshape as desired by a physician or other user of the catheter 330.

The main section 380 of the catheter 330 preferably includes a metalbraid 470 integrally formed or otherwise carried within the polyurethanematerial, as shown in FIGS. 18 and 20. The section 380 may be formed ina standard manner from two concentric tubes (not separately shown) ofpolyurethane, with the braid 470 placed into position in the outer tube,and the inner tube then extruded in position within the braid 470.

The main section 380 is attached to the tip section 390 at a junction480 by means of an adhesive 490, shown in FIG. 20. The first end 450 ofthe elastic stiffener 430 preferably extends a short distance into themain section 380, and enough adhesive 490 is provided both to bind andseal the ends of the sections 380 and 390 where they abut one another atthe junction 480 and to extend from the junction 480 to the first end450 of the stiffener 430, providing a secure adhesion between thestiffener and the electrical connections 350 and 370, on the one hand,and the main section 380, on the other hand. The adhesive 490, which maybe epoxy, cyanoacrylate-related adhesive, or some other appropriateadhesive, when hardened, also serves to stabilize the first end 450 ofthe stiffener 430, in effect anchoring it relative to the main section380.

In order to use the catheter 330, a physician first bends the tip end390 into the configuration he desires. It has been found that agenerally C-shaped tip end is useful for maneuverability. The curvatureof the arc between the first and second end 450 and 460 of the stiffener430 may be greater or less, depending upon the size of the patient. Thetip 390 should be bent such that the stiffener 430 describes theresultant arc along its longer surfaces 500 and 510, rather than alongits shorter surfaces 520 and 530. That is, from the point of view ofFIG. 18, the surface 520 is parallel to the plane of the paper, whereassurfaces 500 and 510 are perpendicular to the plane of the paper. Thesurfaces 520 and 530 thus lie in parallel planes, whereas the broadersurfaces 500 and 510 described the arc between first and second 450 and460 of the stiffener 430. This is highly advantageous for torque controlof the catheter 330 when manipulating it into position. This is becausethe resistance to bending is much less if the bend is made along thesurfaces 500 and 510 (such as in FIG. 18) vis-a-vis the bend being madealong the narrower surfaces 520 and 530. As with the other embodimentsherein, the catheter 330 is radiopaque, and a fluoroscope is used toposition the distal end 440 within the heart. With the configuration ofFIGS. 18-20, it is very easy to predict how the tip section 390 willbend as it meets obstructions or vascular junctions while it is beingpositioned. This greatly increases the ease with which the physician mayposition the catheter 330, and in addition assists the physician inpositioning the distal end 440 against the endocardium for MAPmeasurements.

FIGS. 21-23 show another embodiment of the invention, comprising acatheter 540, with, as in the other embodiments described herein, a tipelectrode 550 and a side electrode 560 electrically connected to plugs(not separately shown) at a proximal end of catheter 540. As with theembodiment shown in FIG. 5, the catheter 540 has a tip portion 570 and aguide wire or stylet 580, which is retractable. The catheter 540 alsoincludes a main portion 590, which is made from a flexible material suchas polyurethane. The tip portion 570 is also from a flexible material,but the materials for tip portions 570 and 590 are chosen such that themain portion 590 is considerably stiffer than the tip portion 570. Themain portion 590 is connected to the tip portion 570 by means of abiocompatible adhesive 595.

The catheter 540 is utilized as follows: the stylet 580, which iscontrolled from the proximal end of the catheter 540, is placed in itsmost distal position, as shown in FIG. 21. A curvature is chosen by thephysician and provided to the distal end of the guide wire 580, much aswith the stiffener 430 shown in FIG. 18. The catheter 540 is thenmaneuvered into the body, such as through the femoral vein. Observingthe catheter through a fluoroscope, the physician may maneuver it upinto the inferior vena cava, as shown in FIG. 22. When a vascularjunction is reached, such as the junction between the hepatic vein andthe inferior vena cava 600, as depicted in FIG. 22, the physician hasthe option of retracting the stylet 580, as shown in FIG. 22. Thematerial of the tip portion 570 is flexible enough so that it willreadily bend over into a bight without damaging or perforating thevascular tissue. Once past such an obstruction, the physician then hasthe option of replacing the stylet 580 at its most distal position.

FIG. 23 shows a very important use for this embodiment of the invention.Once the catheter 540 has reached the tricuspid valve 620 to the rightventrical 630, the stylet 580 is retracted out of the tip portion 570.Thus, the tip portion 570 is inserted into the right atrium 640, and maybe pressed against the tricuspid valve 620 without damage thereto, sincethe tip portion 570 is soft and flexible. As the tricuspid valve opens,the tip portion 570 then springs back into position, such that itsdistal end enters the right ventricle 630. At that point, the catheter540 may be pushed further into the right ventricle 630, and the tipelectrode may then be positioned against the endocardium 650 for makingMAP measurements from the endocardium 650 and the myocardium 660. Atthis point, the physician may withdraw the guide wire or stylet 580entirely, and may insert a different guide wire, such as the stiffenerelement 111 depicted in FIG. 15, with its S-shaped distal end 156 (shownin FIG. 14 from outside the catheter). As discussed above, the S-shapedcurvature is very useful in maintaining the tip of the catheter (such asat electrode 550, shown in FIG. 23) against the endocardium, and forproviding the proper resilience or springiness to maintain contact withthe endocardium as the heart beats.

The force with which the tip of the catheter of the present inventionpresses against the endocardium is optimally within the range of 20-50 gof force. This force is arrived at by balancing two competingconsiderations. The first of these is that the tip electrode (such astip electrode 340 of the catheter 330 shown in FIG. 18) should contactthe endocardium sufficiently strongly that the myocardial cells in thevicinity of the tip electrode 340 are depolarized in a reliable fashion.Balanced against this is the consideration that the tip electrode 340must not penetrate or damage the mycocardium.

A highly useful application for each of the embodiments discussedherein, such as the embodiments of FIGS. 14-23, is in the area ofdisease diagnosis, in particular in the measuring of drug effect (suchas antiarrhythmia drugs) on the heart and in other diagnostic uses, suchas measuring the reaction of the myocardium to varying types of signalsprovided to the pacing electrodes. Such applications are discussed inthe article by E. Platia, M. Weisfeldt and M. Franz (applicant herein)entitled "Immediate Quantitation of Antiarrhythmic Drug Effect byMonophasic Action Potential Recording in Coronary Artery Disease," Am.J. Cardiology 1988; 61; 1284-1287, which is incorporated herein byreference.

FIG. 24 shows an apparatus for standardizing the amount of forcegenerated by the tip 340 pressing against the myocardium when thecatheter 330 is in place. This apparatus and the method for using it areequally applicable to the other embodiments of the catheter of thepresent invention.

A catheter force gauge 70 is shown, and includes a catheter receivingblock 680 mounted thereon, with the block 680 including a groove 690 forreceiving the catheter 330. A clamp 700 is rotatably mounted on theblock 680 at axis 710, and may be tightened by means of a threaded knob720 or other conventional means of clamping.

A gram-force gauge 730 comprises the measuring portion of thecatheter-force gauge 670, and is mounted in a fixed position relative tothe block 680. The gauge 730 includes a measuring arm 740 and a dialindicator 750 of conventional design, wherein force against the arm 740causes a pointer 760 to indicate the amount of force on the dialindicator 750.

In order to utilize the catheter force gauge 670, the know 720 isloosened, and the clamp 700 is rotated out of the way of the groove 690.The catheter 330 is then laid in the groove such that the junction 480between the main section 380 and the tip section 390 lies just at theupper left end 770 of the groove 690. Then the clamp 700 is rotated sothat it overlies the catheter 330, and the knob 720 is tightened to holdthe catheter 330 tightly within the groove 690. The tip electrode 340 isthen placed in a cup-shaped receptacle 780 of the arm 740. It will beunderstood that the length of the arc a described between the tipelectrode 340 and the junction 480 must be somewhat greater than thedistance d between the arm 740 and the upper left end 770 of the groove690. In the preferred embodiment, arc a (i.e., the distance along thelength of the catheter 330 between the tip electrode 340 and thejunction 480) is 4 inches, and the length d is 3 inches.

Once the tip electrode is placed within the receptacle 780, the forcereading will appear on the dial indicator 750. This force will dependupon the type of material utilized for the stiffener 430, as well asupon the configuration thereof, and the shape of the arc a into whichthe distal end of the catheter 330 is bent (i.e., the shape which itretains when not under tension). For instance, if the arc a is a fairlyflat curve, such as a 30° curve, then when the tip electrode 340 hasbeen fitted into the receptacle 780, a reading of, for example, 22 g,may appear on the dial indicator 750, as shown in FIG. 4. However, ifthe distal end of the catheter 330 is bent into a tighter curve-such asa 40° arc-then when the catheter 330 is placed in the gauge 670, a lowerreading on the dial indicator 750 will result, since there is lesstension required to be placed on the elastic stiffener 430 in order toplace the tip electrode 340 into the receptacle 780. In this manner,forces may be measured for a variety of stiffeners and radii ofcurvatures of the distal end of the catheter. Once a physician isacquainted with the approximate amount of curvature for a givenconfiguration of catheter 330 which is necessary to generate the desiredforce, such as 22 g of force, he or she will be able to estimate theamount of force being exerted against the endocardium by the tipelectrode 340 when the catheter 330 is inserted into an in vivo heart,by observing the distal end of the catheter 330 on the fluoroscope.

A variation on the embodiment of FIG. 17 is shown in FIG. 25, whereincorresponding reference numerals are used to refer to identicalstructures. FIG. 25 represents an embodiment wherein the MAP electrodes240 and 250 are not used. An equivalent result may be achieved byutilizing the embodiment shown in FIG. 17, but without utilizing the MAPelectrodes 240 and 250. Applicant has learned that the placement of thepacing electrodes 210 and 220 (as shown in both FIGS. 17 and 25) nearthe tip 230 of the catheter 200 results in a lower threshold voltagebeing required to pace an in vivo heart. Because of this, less power isrequired to pace the heart, resulting in several advantages, includingthe important features that a battery of a portable pacemaker will lastconsiderably longer with the present invention, and that alower-potential pacing signal is less likely to lead to unwantedartefacts. Such a system should also lead to lessened tissue trauma.

Several structural features seem to contribute to the lowering of thepacing threshold, including the feature that the pacing electrodes 210and 220 are positioned substantially on opposite sides of the cathetertip 230, or at least displaced by about a ninety degrees around thecircumference. Applicant believes that the resulting dipole contributesto the lower pacing threshold; thus, other configurations which resultin such a dipole may also be used. In addition, the relatively smallsize of the pacing electrodes 210 and 220 leads to higher surfacecurrent density for a given voltage, again allowing for the lower pacingthreshold. Various shapes of the pacing electrodes may be used (such asdiagonals, squares, straight electrodes parallel or perpendicular to thecatheter body, etc.), the more important characteristics being theirsmall size and their placement relative to the catheter tip and to oneanother.

In applications where the tip 230 of the catheter (or the tip electrode240 as in FIG. 17) is pressed against the endomyocardium, the pacingelectrodes 210 and 220 may strategically be placed a few millimetersfrom the very tip of the catheter (or the tip electrode 240), wherecontact is made with the heart tissue. As discussed above, the pressureof the tip of the catheter on the heart tissue leads to a depolarizationin the vicinity of the pressure, which causes the tissue to be morerefractory, i.e. less responsive to excitation. Thus, it is advantageousto locate the pacing electrodes 210 and 220 away from the region ofdepolarization and toward less refractory, more responsive myocardium,to further contribute to the lowering of the pacing threshold. Whereproximity to the catheter tip of the pacing electrodes is desired, thiswill lead to a balance between locating the electrodes as close to thecatheter tip as possible, and displacing them from the immediate regionof depolarization.

The foregoing description is set forth for the purpose of illustratingthe present invention. However, it should be apparent that numerouschanges can be made in the invention without departing from the scopethereof, as set forth in the appended claims.

I claim:
 1. A system for pacing a heart comprisinga source of a cardiacpacing signal, a catheter body having a distal tip, a first electrodecarried on the catheter body at a first distance of two to sixmillimeters from the distal tip, a second electrode carried on thecatheter body at a second distance of two to six millimeters from thedistal tip and also being located substantially opposite to the firstelectrode, and means connecting the signal source to the first andsecond electrodes for conveying a cardiac pacing signal to the first andsecond electrodes.
 2. A catheter according to claim 1 wherein the firstand second distances are substantially equal.
 3. A catheter according toclaim 1 wherein the first and second electrodes form a dipole.